Aerobic Oxidative N-Heterocyclic Carbene-Catalyzed Formal [3+3] Cyclization for the Synthesis of Tetrasubstituted Benzene Derivatives

Herein, we present an accessible aerobic N-heterocyclic carbene (NHC)-catalyzed method that efficiently produces tetrasubstituted benzene rings in a single reaction. The method employs atmospheric oxygen (O2) as the terminal oxidant in a reaction that requires two oxidative steps. The aerobic oxidation is achieved by a selection of electron transfer mediators orchestrating a redox cascade, turning a high-energy aerobic oxidation reaction pathway into a favorable process.

The response factors (F) were calculated using the following relationship: Atom Economy using atmospheric oxygen as terminal oxidant:

Additional data from the optimization
Enal (1a) and dienone (2a) were used as model substrates for the optimization of the reaction (Scheme 1).
Scheme S1. Overview of reagents and reactants utilised in the optimisation.     General synthetic procedure of the enals (1a-1k) 1 In an oven-dried 100 mL Schlenk flask, 40% ethoxy acetylene solution in hexanes (2.5 equiv., 10 mmol, 2.4 mL) was added under nitrogen atmosphere. The solution was diluted in THF (1.4 mL) and cooled down to 0 °C. 2M solution of borane dimethylsulfide in THF (0.5 equiv., 2 mmol, 1 mL) was added dropwise to the solution of ethoxy acetylene over 30 min at 0 °C. The reaction was warmed to room temperature and stirred for 12 h, then heated to 60 °C for 1 h. When the reaction was cooled down to room temperature, the volatile materials were removed under reduced pressure. The Schlenk flask was put under nitrogen atmosphere and the residue was dissolved in dry toluene (3.8 mL). The reaction was cooled down to -78°C in a bath of dry ice and acetone and 1.1M solution of diethylzinc in toluene (1.8 equiv., 7.2 mmol, 6.5 mL) was added dropwise. After the mixture was stirred for 20 min at -78°C, an acetophenone (1 equiv., 4 mmol) was added. The reaction was warmed to room temperature for 2 hours and stirred for 48 h. After completion of the reaction, it was cooled down to 0 °C and diluted with Et2O (7 mL) and quenched with brine (20 mL). After 10 min of vigorous stirring 2M HCl solution was added dropwise until the solids were dissolved and the pH of the aqueous layer was below 4. The mixture was then stirred for 10 min and monitored by TLC. After completion the aqueous and organic layer were separated, and the organic layer was washed with brine and dried over Na2SO4. The volume was removed under reduced pressure at a temperature under 30°C and the crude was purified using flash column chromatography (Pentane/Ethyl acetate, 4:1) to afford the enal. It's worth noting that these kinds of aldehydes are unstable and need to be stored under nitrogen and in a -80°C freezer.

Synthesis of isocoumarin 8
To 3k (38 mg, 0.116 mmol) in 3 mL of MeOH/H2O (5:1) was added LiOH (20 mg, 0.835 mmol) at room temperature. The reaction mixture was then heated at 70°C for 12 h. After which the reaction mixture was allowed to cool to room temperature and then neutralized (pH = 6) using 1M HCl. The product was extracted with ethyl acetate and washed with brine. The extract was dried with anhydrous MgSO4, evaporated under reduced pressure, and the obtained 3k´ was used directly in the next step without purification.
Scheme S2. Hydrolysis of the ester 3k for the synthesis of the carboxylic acid 3k'.